Bone marrow-derived cells impact metastases formation in pancreatic cancer
MEHNER L. 1, MUNOZ SAGREDO L. 1, ORIAN-ROUSSEAU V. 1
1 Karlsruhe Institute of Technology, Karlsruhe, Germany
Pancreatic cancer is characterized by early dissemination and associated with poor prognosis. The dynamic mutational burden hampers tumor targeting. To successfully develop into metastases, disseminated cancer cells require appropriate niches at distant organs, that support their survival and immune evasion. Metastatic niches are formed, at least in part, by bone marrow derived cells (BMDCs). Tumor-secreted factors or exosomes alter the extracellular matrix (ECM) in distant organs. In turn, the remodeled ECM plays a crucial role in the migration and adhesion of mobilized BMDCs to the distant organ, while BMDCs have been demonstrated to secrete components involved in ECM remodeling, such as fibronectin, collagen and matrix metalloproteinases. Prior the arrival of cancer cells, BMDCs and the remodeled ECM form pre-metastatic niches supporting adhesion, growth, survival and immune evasion of incoming cancer cells.
Our group has shown that inhibition of the cell adhesion molecule CD44, on cancer cells and on host cells, in several mouse and rat pancreatic cancer models, blocked the metastatic process. Additionally, prior to arrival of metastases in target organs, we have detected clusters of BMDCs, which express high levels of CD44.
We are currently assessing the impact of a Cd44 knockout specifically in BMDCs using the Cd44fl/fl; VavCreERT2 inducible mouse model, before and during metastatic niche and metastasis formation. We can show that the removal of Cd44 from BMDCs leads to a drastic reduction in metastasis in vivo. In vitro, using a triple co-culture system including primed BMDCs, pancreatic cancer cells and other cells from the microenvironment, we show that CD44 is involved in CCL2- and CXCL12-mediated migration and VCAM-1- and fibronectin-mediated adhesion.
In both experimental settings, we demonstrate an involvement of CD44 in the immunosuppressive function of BMDCs. Knocking out Cd44 in vitro and in vivo altered the cytokine expression profile of BMDCs and decreased TGF-β-mediated signaling.